Wang, M., Murdoch, C.E., Brewer, A.C. et al. (4 more authors) (2021) Endothelial NADPH oxidase 4 protects against angiotensin II‐induced cardiac fibrosis and inflammation. ESC Heart Failure, 8 (2). pp. 1427-1437. ISSN 2055-5822
Abstract
Aims
Endothelial activation and inflammatory cell infiltration have important roles in the development of cardiac fibrosis induced by renin–angiotensin system activation. NADPH oxidases (Nox proteins) are expressed in endothelial cells (ECs) and alter their function. Previous studies indicated that Nox2 in ECs contributes to angiotensin II (AngII)‐induced cardiac fibrosis. However, the effects of EC Nox4 on cardiac fibrosis are unknown.
Methods and results
Transgenic (TG) mice overexpressing endothelial‐restricted Nox4 were studied alongside wild‐type (WT) littermates as controls. At baseline, Nox4 TG mice had significantly enlarged hearts compared with WT, with elongated cardiomyocytes (increased by 18.5%, P < 0.01) and eccentric hypertrophy but well‐preserved cardiac function by echocardiography and in vivo pressure–volume analysis. Animals were subjected to a chronic AngII infusion (AngII, 1.1 mg/kg/day) for 14 days. Whereas WT/AngII developed a 2.1‐fold increase in interstitial cardiac fibrosis as compared with WT/saline controls (P < 0.01), TG/AngII mice developed significant less fibrosis (1.4‐fold increase, P > 0.05), but there were no differences in cardiac hypertrophy or contractile function between the two groups. TG hearts displayed significantly decreased inflammatory cell infiltration with reduced levels of vascular cell adhesion molecule 1 in both the vasculature and myocardium compared with WT after AngII treatment. TG microvascular ECs stimulated with AngII in vitro supported significantly less leukocyte adhesion than WT ECs.
Conclusions
A chronic increase in endothelial Nox4 stimulates physiological cardiac hypertrophy and protects against AngII‐induced cardiac fibrosis by inhibiting EC activation and the recruitment of inflammatory cells.
Highlights
Mice with endothelium‐specific overexpression of Nox4 (EndoNox4 TG) exhibit eccentric hypertrophy with well‐preserved cardiac function at baseline.
EndoNox4 TG mice develop significantly less interstitial cardiac fibrosis in response to chronic pressure AngII stimulation, independent of cardiac hypertrophy.
Overexpression of Nox4 in endothelial cells reduces AngII‐induced endothelial activation.
An increase in endothelial Nox4 inhibits AngII‐induced recruitment of inflammatory cells in the heart.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/4.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Myocardial fibrosis; Nox4; Endothelial dysfunction; Inflammation; Angiotensin II |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection and Immunity (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 23 Mar 2021 17:05 |
Last Modified: | 15 Feb 2022 16:23 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/ehf2.13228 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:172410 |